Concept: Adrenocorticotropic hormone
- Proceedings of the National Academy of Sciences of the United States of America
- Published over 5 years ago
Cushing disease (CD) is a life-threatening disorder attributed to excess pituitary tumor-derived adrenocorticotrophic hormone (ACTH) and adrenal steroid secretion caused by pituitary tumors. Whereas CD was first described in 1932, the underlying genetic basis driving tumor growth and ACTH secretion remains unsolved. Here, we show that testicular orphan nuclear receptor 4 (TR4, nuclear receptor subfamily 2, group C, member 2) is overexpressed in human corticotroph tumors as well as in human and mouse corticotroph tumor cell lines. Forced overexpression of TR4 in both human and murine tumor cells increased proopiomelanocortin transcription, ACTH secretion, cellular proliferation, and tumor invasion rates in vitro. Conversely, knockdown of TR4 expression reversed all phenotypes. Mechanistically, we show that TR4 transcriptionally activates proopiomelanocortin through binding of a direct repeat 1 response element in the promoter, and that this is enhanced by MAPK-mediated TR4 phosphorylation. In vivo, TR4 overexpression promotes murine corticotroph tumor growth as well as enhances ACTH and corticosterone production, whereas TR4 knockdown decreases circulating ACTH and corticosterone levels in mice harboring ACTH-secreting tumors. Our findings directly link TR4 to the etiology of corticotroph tumors, hormone secretion, and cell growth as well as identify it as a potential target in the treatment of CD.
Most species living in temperate zones adapt their physiology and behavior to seasonal changes in the environment by using the photoperiod as a primary cue. The mechanisms underlying photoperiodic regulation of stress-related functions are not well understood. In this study, we analyzed the effects of photoperiod on the hypothalamic-pituitary-adrenal axis in photoperiod-sensitive Fischer 344 rats. We first examined how photoperiod affects diurnal variations in plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone. ACTH levels did not exhibit diurnal variations under long- and short-day conditions. On the other hand, corticosterone levels exhibited a clear rhythm under short-day condition with a peak during dark phase. This peak was not observed under long-day condition in which a significant rhythm was not detected. To analyze the mechanisms responsible for the photoperiodic regulation of corticosterone rhythms, ACTH was intraperitoneally injected at the onset of the light or dark phase in dexamethasone-treated rats maintained under long- and short-day conditions. ACTH induced higher corticosterone levels in rats examined at dark onset under short-day condition than those maintained under long-day condition. Next, we asked whether melatonin signals are involved in photoperiodic regulation of corticosterone rhythms, and rats were intraperitoneally injected with melatonin at late afternoon under long-day condition for 3 weeks. However, melatonin injections did not affect the corticosterone rhythms. In addition, photoperiodic changes in the amplitude of corticosterone rhythms were also observed in melatonin-deficient C57BL/6J mice, in which expression profiles of several clock genes and steroidgenesis genes in adrenal gland were modified by the photoperiod. Our data suggest that photoperiod regulates corticosterone rhythms by altered adrenal sensitivity through melatonin-independent mechanisms that may involve the adrenal clock.
The non-invasive measurement of adrenocortical function in cheetahs is an important tool to assess stress in captive and free-ranging individuals, because stress has been suggested to be one of the causes of poor reproductive performance of captive cheetahs. We tested four enzyme immunoassays (EIA) in two captive cheetahs in Germany using adrenocorticotropic hormone (ACTH) challenges and identified the corticosterone-3-CMO EIA to be most sensitive to the increase in faecal glucocorticoid metabolite (fGCM) concentrations after the ACTH challenge. This EIA performed also well in five captive cheetahs in South Africa. The fGCM concentrations across all seven cheetahs increased within 24h by 681% compared to the baseline levels prior to ACTH. Storage of faecal samples at 0-4°C did not strongly affect fGCM concentrations within 24h, simplifying sample collection when immediate storage at -20°C is not feasible. The two cheetahs in Germany also received an injection of [(3)H]cortisol to characterise fGCMs in faecal extracts using high-performance liquid chromatography (HPLC) immunograms. HPLC fractions were measured for their radioactivity and immunoreactive fGCM concentrations with the corticosterone-3-CMO EIA, respectively. The results revealed a polar peak of radiolabelled cortisol metabolites co-eluting with the major peak of immunoreactive fGCMs. Thus, our EIA measured substantial amounts of fGCMs corresponding to the radioactive peaks. The peaks were of higher polarity than native cortisol and corticosterone, suggesting that the metabolites were conjugated, which was confirmed by solvolysis of the HPLC fractions. Our results show that the corticosterone-3-CMO EIA is a reliable tool to assess fGCMs in cheetahs.
The Adrenocorticotropic hormone (ACTH) and Pro-opimelanocortin (POMC) 1-28 N-terminal peptide (N-POMC(1-28)) have been shown to act as an adrenal mitogen in vivo. A possible role for cyclin E in the zona glomerulosa (ZG) proliferation, following ACTH and/or N-POMC(1-28) administration, has been previously demonstrated. In this study, we investigated the effect of ACTH and N-POMC(1-28) on the expression of adrenal cortex proteins related to cell cycle control such as cyclins D and P27(kip1). The administration of N-POMC upregulated cyclin D1 and D2 expression in the outer zone of the adrenal cortex; cyclin D3 expression was upregulated in the cortex inner zone even after administration of ACTH. Both ACTH and N-POMC peptides induced a decrease in the P27(kip1) expression in the ZG. These novel findings suggest that the POMC-derivate peptides, ACTH and N-POMC, promote proliferation in the adrenal cortex by upregulating the D2 and D3 cyclins and downregulating the P27(kip1) expression.
Aging is associated with decline in cardiovascular, autonomic function, and brain-derived neurotropic factor (BDNF). Reports are scanty regarding whether yoga can improve age-related degenerative changes in healthy active men. This study is designed to appraise the role of yoga in improving age-related degenerative changes in cardiometabolic risk profile, autonomic function, stress, and BDNF. Healthy active males of three age groups (20-29, 30-39, and 40-49 years) were randomly assigned to practice yoga daily 1 h for 3 months. Significantly higher values of heart rate (HR), blood pressure (BP), load in heart (DoP), myocardial oxygen consumption (RPP), and total cholesterol (TC) were noted in senior age group. HR, BP, DoP, RPP, and TC decreased significantly following yogic practice. High frequency (HF), total power (TP), all time domain variables of heart rate variability (HRV), and skin conductance (SC) were significantly decreased with advancement of age. HF, TP, and time domain parameters of HRV and SC increased significantly following yogic practice. Higher levels of catecholamines and low frequency (LF) power of HRV was noted with advancement of age. Levels of catecholamines and LF significantly decreased following yogic practice. Cortisol and adrenocorticotropic hormone (ACTH) level raised in senior age group. BDNF, serotonin, and dopamine were low in higher age group. Significant decrement of cortisol; ACTH; and increment in serotonin, dopamine, and BDNF was noted following yogic practice. This study revealed that yogic practices might help in the prevention of age-related degeneration by changing cardiometabolic risk factors, autonomic function, and BDNF in healthy male.
ACTH independent macronodular adrenal hyperplasia (AIMAH) is a rare disorder characterized by bilateral macronodular hyperplasia of the adrenal glands and increased cortisol production with subclinical or overt Cushing’s syndrome. Although the family clustering of AIMAH is infrequent, we have tried our best to find such a familial affected pedigree with complete clinical information and successfully collect adrenalectomy tissue samples from two members of this family. Using whole exome sequencing and several variant prioritization strategies based on disease network analysis, we identified Endothelin receptor type A (EDNRA) Ser420Thr mutation as a causative mutation of AIMAH. EDNRA is a member of G protein coupled receptor family and is involved in cardiovascular or polycystic kidney disease. Our findings indicate that the mutation of EDNRA at S420T site should be regard as a potential AIMAH causative variation in familial and sporadic affected patients.
Objective: To report a patient who had developed reversible hypocortisolism during the use of quetiapine.Methods: Early morning cortisol levels were measured on two separate days. In addition, the patient underwent testing with intravenous synthetic adrenocorticotropic hormone (1 g tetracosactide) before and after tapering of quetiapine. Pituitary function was assessed and MR imaging was performed.Results: At presentation, when the patient used quetiapine he had low early morning cortisol levels. Tetracosactide testing indicated hypocortisolism. MR imaging of the pituitary was unremarkable. The patient was treated temporarily with hydrocortisone and quetiapine was tapered. After quetiapine had been discontinued, the patient’s cortisol production had returned to normal.Conclusion: Although lowering of cortisol levels has been reported, this is the first report of hypocortisolism associated with the use of quetiapine. Possibly, symptoms of malaise in patients who use quetiapine could be attributed to quetiapine-related hypocortisolism.
The diagnostic accuracy of dehydroepiandrosterone sulfate (DHEAS) to predict subclinical Cushing’s syndrome (sCS) has been a matter of debate. The primary objective of this study was to assess the diagnostic power of DHEAS in predicting sCS. This retrospective study was conducted in a tertiary referral center and based on subjects referred between 2004 and 2014. Data of 249 subjects with adrenal incidentalomas were evaluated. We also reviewed 604 DHEAS measurements from adults, which were performed during the same period in our laboratory (LB group). Adrenocortical function, tumor size, and clinical characteristics were assessed. We diagnosed sCS in 15.2 % of the participants in the presence of ≥2 of the following; 1 mg dexamethasone suppression test >3.0 μg/dl, urinary free cortisol >70 μg/24 h, and corticotrophin (ACTH) <10 pg/ml. DHEAS levels were significantly reduced in patients with sCS (n = 38) compared to sCS (-) (n = 141) and LB groups (n = 604) (27.95, 65.90, and 66.80 µg/dl, respectively, p < 0.001) while age was comparable. The ROC curve analysis showed that the cut-off of the DHEAS with the best diagnostic accuracy for detecting sCS was 40.0 μg/dl (SN, 68 %; SP, 75; PPV, 43 %; NPV, 90 %, AUC: 0.788, p < 0.001). Logistic regression assessed the impact of age, BMI, low DHEAS (<40 μg/dl), bilateral tumors, and tumor size on the likelihood of having sCS. The strongest predictor was low DHEAS, recording an OR of 9.41. DHEAS levels are inversely associated with the extent of cortisol excess. In subjects with intermediate laboratory findings, detection of low DHEAS could be advantageous for distinguishing sCS.
Sutherlandia frutescens is widely used in indigenous medicine for the treatment of stress- and anxiety-related disorders, and although anecdotal evidence has been scientifically confirmed, relatively little data are available on its potential mechanisms of action. We manipulated a rodent model of acute psychological stress by acutely administering a low dose (4 mg/kg body mass) of S. frutescens extract 30 min prior to stress exposure (1 h restraint), to elucidate both its central and peripheral mechanisms of action in the context of acute stress. After 1 h of exposure to stress, acute restraint resulted in a significant increase in plasma corticosterone levels (56 ± 33 versus 499 ± 50 ng/ml; P < 0.0001) and anterior pituitary adrenocorticotropic hormone (ACTH) levels (0.066 ± 0.017 versus 0.202 ± 0.033% fluorescent area; P = 0.07), while decreasing hippocampal glucocorticoid receptor (GR) and gamma-aminobutyric acid (GABA)(A)α1 receptor levels (both P < 0.05). While the low dose of S. frutescens administered did not seem to have an effect on the down-stream stress response, it abolished the stress-induced down-regulation of GR, in a manner independent of GABA(A)α1 receptor. Results suggest a non-sedative effect of low-dose S. frutescens and points to central mechanisms of action that is in support of the anecdotal claims for its effectiveness as complimentary treatment in chronic stress-associated diseases.
Patients with rare defects in the gene encoding proopiomelanocortin (POMC) have extreme early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism, resulting from the lack of the proopiomelanocortin-derived peptides melanocyte-stimulating hormone and corticotropin. In such patients, adrenal insufficiency must be treated with hydrocortisone early in life. No effective pharmacologic treatments have been available for the hyperphagia and obesity that characterize the condition. In this investigator-initiated, open-label study, two patients with proopiomelanocortin deficiency were treated with setmelanotide, a new melanocortin-4 receptor agonist. The patients had a sustainable reduction in hunger and substantial weight loss (51.0 kg after 42 weeks in Patient 1 and 20.5 kg after 12 weeks in Patient 2).